Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), characterized clinically by relapses and remissions, often leading to progressive physical impairment. MS is the most common disabling neurological disorder affecting young white adults. At least 350,000 Americans have MS, with women affected twice as often as men. MS usually starts by the ages of 15 and 50; the average age of onset is 30. The risk of MS varies for different geographical areas and one increases as one lives further north or south of the equator.
The precise etiology and pathogenesis of the disease remain unknown; however, pathologic, genetic, and immunologic features have been identified which suggest that the disease has an autoimmune basis; see e.g., Waksman, et al., Proc. Soc. Exp. Biol. Med., 175:282-294 (1984) and Hafler et al., Immunol. Rev., 100:307-332 (1987). MS follows a varied, often unpredictable course, but is typically categorized into four widely recognized forms: relapsing-remitting (.about.25% of cases); relapsing-progressive (.about.40% of cases); chronic-progressive (.about.15% of cases); and benign (.about.20% of cases). Nearly all MS patients suffer such symptoms as fatigue, spasticity, tremor, decreased mobility, depression, pain, urologic complications, and cognitive impairment at some point during the course of their disease.
MS is currently incurable, but it is largely treatable. Most treatments are symptomatic; that is, they relieve or prevent a symptom, without being able to repair the underlying defect of demyelination, although corticosteroids and broad immunosuppressants demonstrate transitory, disease-altering benefits. Corticosteroids can reduce the duration of disease flare-ups while some immunosuppressants, e.g., Burroughs-Wellcome's Imuran.RTM., are reputed to lesson the number of such flare-ups experienced by MS patients.
Interferons are a subclass of cytokines that exhibit both antiviral and antiproliferative activity. On the basis of biochemical and immunological properties, the naturally-occurring human interferons are grouped into three classes: interferon alpha (leukocyte), interferon beta (fibroblast) and interferon gamma (immune). Alpha-interferon is currently approved in the United States and other countries for the treatment of hairy cell leukemia, venereal warts, Kaposi's Sarcoma (a cancer commonly afflicting patients suffering from Acquired Immune Deficiency Syndrome (AIDS)), and chronic non-A, non-B hepatitis. Two variants of alpha interferon have received approval for therapeutic use: Interferon alfa-2a, marketed under the trade name Roferon.RTM.-A, and Interferon alfa-2b, marketed under the trade name INTRON.RTM. A. The amino acid sequences of Roferon.RTM.-A and INTRON.RTM. A differ at a single position but otherwise are identical to the amino acid sequence of alpha-interferon subtype 2 (subtype A).
In addition to the labeled indications, alpha-interferon is being used or evaluated alone or in conjunction with chemotherapeutic agents in a variety of other cellular proliferation disorders, including chronic myelogenous leukemia, multiple myeloma, superficial bladder cancer, skin cancers (basal cell carcinoma and malignant melanoma), renal cell carcinoma, ovarian cancer, low grade lymphocytic and cutaneous T cell lymphoma, and glioma. Alpha-interferon may be effective in combination with other chemotherapy agents for the treatment of solid tumors that arise from lung, colorectal and breast cancer (see Rosenberg et al. "Principles and Applications of Biologic Therapy" in Cancer: Principles and Practices of Oncology, 3rd ed., Devita et al., eds. pp. 301-547 (1989), Balmer DICP, Ann Pharmacother 24, 761-768 (1990)).
Type 1 interferons (e.g. interferon alpha and interferon beta) are known to affect a variety of cellular functions, including DNA replication and RNA and protein synthesis, in both normal and abnormal cells. Thus, cytotoxic effects of interferon are not restricted to tumor or virus infected cells but are also manifested in normal, healthy cells as well. As a result, undesirable side effects arise during interferon therapy, particularly when high doses are required. Administration of interferon can lead to myelosuppression resulting in reduced red blood cell, white blood cell and platelet levels. Higher doses of interferon commonly give rise to flu-like symptoms (e.g., fever, fatigue, headaches and chills), gastrointestinal disorders (e.g., anorexia, nausea and diarrhea), dizziness and coughing. It would be useful to reduce or eliminate the undesirable side effects of interferon therapy without diminishing the therapeutic benefits of such therapy.
Betaseron.RTM. (Schering Corp's recombinant interferon beta-1b) was the first drug indicated specifically for the treatment of MS. In a major clinical trial, Betaseron.RTM. was found to be effective in reducing the number and severity of exacerbations, or relapses, suffered by MS patients, as well as decreasing magnetic resonance imaging (MRI) evidence of MS activity in the brain. Importantly, the results of the trial pertained only to the relapsing-remitting patient group, since other forms of MS were not represented in the trial. Moreover, the trial demonstrated no beneficial effect of the drug on ultimate disability of MS over the 2 to 3 years of the study, and the effectiveness of the drug is significantly impaired by its side effects.
U.S. Pat. Nos. 4,695,623, 4,897,471 and 5,541,293 disclose novel human interferon polypeptides having amino acid sequences which include common or predominant amino acids found at each position among naturally-occurring alpha interferon subtype polypeptides and are referred to as consensus interferons (IFN-con). The IFN-con amino acid sequences disclosed are designated IFN-con.sub.1, IFN-con.sub.2, and IFNcon.sub.3. The preparation of manufactured genes encoding IFN-con and the expression of said genes in E. coli are also disclosed. In vitro studies comparing the relative antiviral, antiproliferative, and natural killer cell activities of recombinant IFN-con with either leukocyte or other recombinant type-one interferons demonstrate that IFN-con displays significantly higher activity when compared on a mass basis; Ozes et al., J Interferon Research, 12:55-59, 1992.
U.S. Pat. No. 5,372,808 discloses methods of treatment of diseases using consensus interferon. It is shown that IFN-con, when used in the treatment of diseases susceptible to treatment by alpha interferons, does not cause the same degree of side effects in patients as do the alpha interferons. It was further shown that 3 to 5 times higher doses of IFN-con can be used, leading to enhanced therapeutic benefit, with substantially no corresponding increase in the frequency or severity of undesirable side effects.